Heart failure is associated

Transcription

1 THE C ONTROVERSIAL Heart failure is associated with impaired quality of life, high morbidity, mortality, and frequent hospitalization. Implementation of evidence-based, guideline-recommended therapy is important to prevent the worst clinical outcomes related to HF. HF guidelines recommend that, during uptitration, the doses of ACE inhibitors/arbs, β-blockers, and MRAs should be doubledevery 2-4 weeks. However, different clinical conditions and drug tolerability may complicate and slow titration in clinical practice. Strict observance of titration algorithms in heart failure is preventing the rapid initiation of guideline-recommended therapy: a missed opportunity for optimal protection? 1. J. Zhou and J. Ge, China 2. S. M. Kang, Korea 3. Y. Lopatin, Russian Federation 4. G. P. Perna, Italy 5. M. A. Saleh, Egypt 6. P. V. Schwartzmann, Brazil 7. H. S. Sisakian, Armenia 8. M. Zoghi, Turkey Strict observance of titration algorithms: a missed opportunity for optimal protection? MEDICOGRAPHIA, Vol 40, No. 1,

2 1. J. Zhou, J. Ge, China heart rate 70 bpm at baseline, 54.4% were on b-blockers, and 80.2% still had a heart rate 70 bpm at discharge, making heart rate at discharge a potential target for treating HF. Jingmin ZHOU, MD (left) - Junbo GE, MD (right) Department of Cardiology, Zhongshan Hospital, Fudan University Shanghai , CHINA ( jbge@zs-hospital.sh.cn) T he prevalence and mortality rate of heart failure continues to grow rapidly in China, with nearly 4.5 million people affected. The China National Heart Failure Registry shows that 74.7% of patients had an NYHA functional classification of grade II to IV. All guidelines for the management of acute and chronic HF provide a therapeutic algorithm for a patient with symptomatic HFrEF, whereby ACE inhibitors (ARBs when intolerant to ACE inhibitors) and b- blockers are the treatment cornerstones. Treatment should be initiated with a very low dose and then uptitrated to the maximum tolerated evidence-based dose. After this uptitration period, if the patient is still symptomatic and the LVEF is 35%, MRAs should be used for aldosterone escape and then ivabradine for sinus rate control. The QUALIFY study showed that, for the Chinese group, the rate of b-blocker use was 82%, with only 10% reaching the target dose, and the average heart rate was 78.4 bpm. 1 b-blockers are often initiated before patient discharge; however, due to their negative inotropic effects, the dose should be increased every 2 to 4 weeks until the target dose or highest tolerated dose is reached. However, patients in this phase are often fragile, with dyspnea, fatigue, palpitation with low-level activity, and a high heart rate. A high heart rate increases myocardial stress and oxygen demand and decreases the oxygen supply during diastole, which decreases myocardial contraction and impairs heart function; whereas, a low heart rate prolongs the diastolic time and improves coronary blood flow and oxygen supply. Habal et al 2 showed that a high heart rate ( 81 bpm) at discharge was associated with a significant increase in all-cause, 30-day, and 1-year mortality and hospital readmissions. In a retrospective, cohort study, the association between discharge heart rate and mortality was significant both at 0 to 30 days and 31 to 365 days in patients with a heart rate 75, with a higher risk occurring in the first 30 days. 3 The OPTIMIZE- HF registry 4,5 showed that the median discharge heart rate was 76 bpm, with 73% of the patients taking a b-blocker. The ASCEND-HF trial 6 showed that 85.8% of the patients had a Ivabradine reduces heart rate by inhibiting the I f channel in the sinus node, with no effect on myocardial contraction or blood pressure. In patients with acute decompensated systolic HF and a resting heart rate >70 bpm, the early (within 24 hours) and late (at discharge) oral administration of ivabradine was safe and efficient for reducing heart rate, improving the NYHA class, and reducing the NT-proBNP. 7 In patients hospitalized with HFrEF, early treatment with ivabradine plus b-blockers vs b-blockers alone significantly decreased heart rate and increased the ejection fraction at 28 days and 4 months and significantly decreased BNP levels at 4 months. 8 Bagriy et al 9 showed that patients with HF and LV dysfunction had a lower heart rate and a better exercise capacity at 5 months when treated with ivabradine plus carvedilol vs carvedilol alone, meanwhile a higher carvedilol uptitration dosage was reached. No severe side effects attributable to the early administration of ivabradine were observed. These data show a benefit of early heart rate control in patients with HFrEF and a high heart rate before the maximum of b-blocker dose is reached. Given the large proportion of patients with HFrEF and a high heart rate at discharge in the real world, the early administration of ivabradine to achieve the heart rate goal will greatly improve the patient s prognosis and will be the hot topic of current clinical practice. 1. Komajda M, Anker SD, Cowie MR, et al. Physicians adherence to guideline-recommended medications in heart failure with reduced ejection fraction: data from the QUALIFY global survey. Eur J Heart Fail. 2016;18(5): Habal MV, Liu PP, Austin PC, et al. Association of heart rate at hospital discharge with mortality and hospitalizations in patients with heart failure. Circ Heart Fail. 2014;7(1): Laskey WK, Alomari I, Cox M, et al. Heart rate at hospital discharge in patients with heart failure is associated with mortality and rehospitalization. J Am Heart Assoc. 2015;4(4). pii: e DeVore AD, Mi X, Mentz RJ, et al. Discharge heart rate and b-blocker dose in patients hospitalized with heart failure: findings from the OPTIMIZE-HF registry. Am Heart J. 2016;173: Fonarow GC, Abraham WT, Albert NM, et al. Carvedilol use at discharge in patients hospitalized for heart failure is associated with improved survival: an analysis from OPTIMIZE-HF. Am Heart J. 2007;153(1):82.e1-e Kitai T, Grodin JL, Mentz RJ, et al. Insufficient reduction in heart rate during hospitalization despite beta-blocker treatment in acute decompensated heart failure: insights from the ASCEND-HF trial. Eur J Heart Fail. 2017;19(2): Sargento L, Satendra M, Longo S, Lousada N, dos Reis RP. Heart rate reduction with ivabradine in patients with acute decompensated systolic heart failure. Am J Cardiovasc Drugs. 2014;14(3): Hidalgo FJ, Anguita M, Castillo JC, et al. Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalised with heart failure and reduced left ventricular ejection fraction (ETHIC-AHF): a randomised study. Int J Cardiol. 2016;217: Bagriy AE, Schukina EV, Samoilova OV, et al. Addition of ivabradine to b-blocker improves exercise capacity in systolic heart failure patients in a prospective, openlabel study. Adv Ther. 2015;32(2): MEDICOGRAPHIA, Vol 40, No. 1, 2018 Strict observance of titration algorithms: a missed opportunity for optimal protection?

3 2. S. M. Kang, Korea Seok Min KANG, MD, PhD Director, Heart Failure Center, Cardiac Wellness Center and Cardiac Rehabilitation Clinic Professor and Chief, Cardiology Division Severance Cardiovascular Hospital Yonsei University Medical College Seoul, KOREA ( T he prevalence of heart failure continues to rise due to increasing rates of heart failure risk factors, such as diabetes, obesity, chronic kidney disease, hypertension, and better survival in patients with cardiovascular disease. 1 Current heart failure management guidelines recommend the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), b-blockers, and mineralocorticoid receptor antagonists (MRAs) for reducing the mortality of patients with heart failure with a reduced left ventricular ejection fraction (HFrEF), based on large-scale randomized controlled clinical studies. Thus, implementation of guidelinerecommended medical therapy for heart failure, including drug uptitration to the target doses, has been associated with improved clinical outcomes in patients with HFrEF. 2,3 However, in the real-world setting, clinicians have generally worried about the uptitration of b-blockers, especially in a relatively acute phase of heart failure, due to negative inotropic agents. Furthermore, for HFrEF patients with hypotension, chronic kidney disease, and poor drug tolerability, it is more difficult to uptitrate these evidence-based medications. In addition, when it comes to starting these medications, the major concerns of clinicians are determining which medication should be given first, what is the optimal timing to initiate medication, and which interval is optimal for uptitration. According to several studies, only a small proportion of patients with HFrEF are on target doses of ACE inhibitors/arbs, b-blockers, and MRAs at the time of discharge. 4 In addition, uptitration at an outpatient clinic is not readily available due to the lack of a patient-specific titration plan, poor communication of the medication plan between doctors and patients, difficulty in managing adverse effects associated with increasing doses, and patient adherence due to the changing medication regimen. This titration gap is partly explained by higher rates of drug intolerance in elderly patients with multiple comorbidities, low body mass index, and polypharmacy who are excluded from clinical trials. Over the past two decades, the prescription rate of ACE inhibitors/arbs, b-blockers, and MRAs has improved greatly. However, the doses prescribed are much lower than the target doses recommended by heart failure guidelines, the uptitration has not been achieved, or the medications have even been discontinued in clinical practice. Therefore, we need to find a tailored drug treatment strategy to improve medication adherence and uptitration that can reduce the mortality or rehospitalization after discharge in these patients. Thus, the set-up of a transitional care system that helps patients pick up and start prescribed medications is very important. A multidisciplinary team based approach before discharge or through a specialized heart failure outpatient clinic, including nursing and pharmacy support, can play an important role in drug uptitration by supporting the patient s treatment adherence and optimizing evidence-based treatments by using tools, such as an individualized heart failure medication titration plan. 5 Medication titration plans should be completed by the patient s treating health care team and outline a suggested schedule for titration, target doses for heart failure medicines, required monitoring, and management of common adverse effects. The population of Asia is growing both larger and older. People 65 years old will make up an increasingly large percentage of the Asian population in the subsequent years, especially in Korea and Japan. Asian patients with heart failure have different treatment responses or strategies according to a different medical culture and health care system; therefore, this should be considered in the guideline-recommended therapy for these patients. 1. Roger VL. Epidemiology of heart failure. Circ Res. 2013;113(6): Ponikowski P, Voors AA, Anker SD, et al ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37(27): Yancy CW, Jessup M, Bozkurt B, et al ACCF/AHA guideline for the management of heart failure. J Am Coll Cardiol. 2013;62(16): Fonarow GC, Yancy CW, Hernandez AF, Peterson ED, Spertus JA, Heidenreich PA. Potential impact of optimal implementation of evidence-based heart failure therapies on mortality. Am Heart J. 2011;161(6): Takeda A, Taylor SJ, Taylor RS, Khan F, Krum H, Underwood M. Clinical service organization for heart failure. Cochrane Database Syst Rev. 2012;12(9):CD Strict observance of titration algorithms: a missed opportunity for optimal protection? MEDICOGRAPHIA, Vol 40, No. 1,

4 3. Y. Lopatin, Russian Federation Yury LOPATIN, MD, PhD, FHFA Professor and Head of the Cardiology Department of Volgograd State Medical University, Head of the Department No. 1 of Volgograd Regional Cardiology Centre Volgograd, RUSSIAN FEDERATION ( yu.lopatin@gmail.com) T here is no doubt that prescribing evidence-based, guideline-recommended therapies is the most effective strategy for preventing mortality and hospital admissions for patients with heart failure. However, even if we consider the usage rate of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), b-blockers, and mineralocorticoid receptor antagonists (MRAs) as satisfactory, it is well known that a high proportion of patients with heart failure are not treated with target doses, but suboptimal doses of these drugs. 1 Indeed, according to the international QUAL- IFY survey (QUality of Adherence to guideline recommendations for LIFe-saving treatment in heart failure survey), the proportion of patients at the target doses and 50% of the target doses was low (27.9% and 63.3% for ACE inhibitors, 6.9% and 39.5% for ARBs, and 14.8% and 51.8% for b-blockers, respectively). 2 Moreover, a subsequent analysis of the QUAL- IFY data showed that poor adherence to recommended doses of heart failure medications was associated with a significantly higher overall, cardiovascular, and heart failure mortality, combined heart failure hospitalization or heart failure death and cardiovascular hospitalization or cardiovascular death. 3 Different factors may be responsible for the underdosing of guideline-recommended classes of heart failure medications, such as patient-related (eg, poor tolerability and compliance related to comorbidities, aging, or frailty), physician-related (eg, reluctance to provide disease-modifying agents and focus on symptom relief), and health care related (eg, access to specialized heart failure care, cost of medications, reimbursement schemes) factors. A rigorous plan for dose uptitration of guideline-recommended therapies that requires many visits and careful monitoring may also be considered as an important factor contributing to the underdosing of heart failure medications. Indeed, heart failure guidelines recommend starting with low doses of ACE inhibitors/arbs, b-blockers, and MRAs and doubling them at not less than 2- to 4-week intervals. 4 In addition, heart failure guidelines allow for a more rapid uptitration of ACE inhibitors (or ARBs), but not of b-blockers and MRAs in hospitalized patients who are closely monitored. As a result, at hospital discharge, a high proportion of patients continue to have a heart rate 70 bpm, which is associated with worse 1-year outcomes and increased direct medical costs. 5 Moreover, even after an aggressive b-blocker uptitration for several months, an effective heart rate control was not achieved in many patients with heart failure. 6 In these patients, a persisting high heart rate was also associated with worse clinical outcomes. 6 Does this mean we should abandon the strict titration algorithm of guideline-recommended classes of heart failure medications? Of course not! Primarily, it is needed in cases when a more rapid uptitration of ACE inhibitors (or ARBs), but not of b-blockers and MRAs, is impossible. However, it cannot be an excuse for not prescribing or for delaying the initiation of guideline-recommended heart failure therapies. A good example of the effective optimization of a rigorous plan for dose uptitration of heart failure medications is an early coadministration of b-blockers and ivabradine during hospital admission, which results in an improvement in the New York Heart Association functional class, left ventricular systolic function, and, most importantly, an improvement in outcomes following a heart failure hospitalization. 7,8 Obviously, a titration algorithm for heart failure medications may be more flexible, especially if we are talking about heart rate lowering therapy. 1. Maggioni AP, Anker SD, Dahlström U, et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long- Term Registry. Eur J Heart Fail. 2013;15(10): Komajda M, Anker SD, Cowie MR, et al; QUALIFY Investigators. Physicians adherence to guideline-recommended medications in heart failure with reduced ejection fraction: data from the QUALIFY global survey. Eur J Heart Fail. 2016; 18(5): Komajda M, Cowie MR, Tavazzi L, et al; QUALIFY Investigators. Physicians guideline adherence is associated with better prognosis in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry. Eur J Heart Fail. 2017;19(11): Ponikowski P, Voors AA, Anker SD, et al ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 2016;18(8): DeVore AD, Schulte PJ, Mentz RJ, et al. Relation of elevated heart rate in patients with heart failure with reduced ejection fraction to one-year outcomes and costs. Am J Cardiol. 2016;117(6): Ibrahim NE, Januzzi JL, Rabideau DJ, Gandhi PU, Gaggin HK. Serial heart rates, guideline-directed beta blocker use, and outcomes in patients with chronic heart failure with reduced ejection fraction. Am J Cardiol. 2017;120(5): Hidalgo FJ, Anguita M, Castillo JC, et al. Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalised with heart failure and reduced left ventricular ejection fraction (ETHIC- AHF): a randomised study. Int J Cardiol. 2016;217: Cowie MR, Lopatin YM, Saldarriaga C, et al. The Optimize Heart Failure Care Program: initial lessons from global implementation. Int J Cardiol. 2017;236: MEDICOGRAPHIA, Vol 40, No. 1, 2018 Strict observance of titration algorithms: a missed opportunity for optimal protection?

5 4. G. P. Perna, Italy Gian Piero PERNA, MD Cardiology Department Ospedali Riuniti Ancona ITALY ( H eart failure with reduced ejection fraction (HFrEF) is the result of various clinical conditions, all of which have the common characteristics of reduced myocardial function, typical symptoms, frequent hospitalizations, and high mortality and morbidity. Moreover, HFrEF may be considered as a systemic condition in which neurohormonal activation, hemodynamic alterations, elevated heart rate, and myocardial toxicity mediate cardiac remodeling and disease progression. Over the last 30 years, the implementation of guideline-recommended therapies have improved survival and reduced the hospitalization rate in patients with HFrEF, although the outcome often remains unsatisfactory. 1 Effective treatments for HFrEF include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists (MRAs), angiotensin-receptor/neprilysin inhibitors, b-blockers, ivabradine, and devices (cardiac resynchronization therapy or implantable cardioverter defibrillators). 1 These strategies are flanked by symptomatic treatment, in particular diuretics. Neurohormonal antagonists are recommended as a first-line therapy for every patient with HFrEF, unless contraindicated or not tolerated. The current guidelines recommend that the uptitration of ACE inhibitors/arbs, b-blockers, and MRAs be done slowly, doubling the doses every 2 to 4 weeks. However, in clinical practice, many patients with HFrEF assume low doses of effective treatments (<50% of the target doses), especially b-blockers. 2 Different clinical conditions, compliance, and organizational problems may complicate and slow b-blocker uptitration, thus delaying initiation of some guideline-recommended therapies, such as ivabradine in patients in sinus rhythm with a heart rate >70 bpm; these patients represent at least 20% of the overall population in clinical practice. 3 An elevated heart rate is a risk factor in patients with HFrEF 1 because it increases myocardial oxygen consumption, reduces diastole duration, myocardial perfusion, and ventricular filling, and worsens left ventricular ejection fraction (LVEF) and left intraventricular dyssynchrony. 3 Reducing heart rate can counteract such adverse effects, and part of the favorable effects of b-blockers are due to a decrease in heart rate. 3 Nevertheless, as the uptitration of b-blockers is not achievable in many patients, 2 there is an urgent need for complementary therapeutic strategies to reduce heart rate. 3 The early introduction of ivabradine in association with b-blockers may allow a faster and more complete uptitration of b-blockers, a greater reduction in heart rate, and significant improvements in LVEF and exercise capacity. 4 In our clinical experience, some patients respond better to an earlier addition of ivabradine to b-blockers (ie, patients with a systolic blood pressure (SBP) <110 mm Hg, HFrEF due to chemotherapy and/or anemia, patients with chronic obstructive pulmonary disease, patients with HFrEF and high pulmonary artery pressure, and in-hospital patients with acute or decompensated heart failure). In patients with an SBP <110 mm Hg and HFrEF due to chemotherapy agents and/or anemia, the early addition of ivabradine reduces some side effects (eg, asthenia, peripheral hypoperfusion, increase in pulmonary pressure, bronchospasm) and facilitates b-blocker uptitration, with more patients reaching >50% of the target dose and target heart rate within 4 weeks. At the same time, more patients had significant increases in SBP, decreases in pulmonary artery pressure, and improvements in LVEF and symptoms. Therefore, when added earlier, ivabradine is an interesting example of therapeutic integration, in which the further reduction in heart rate leads to sympathetic modulation, without affecting cardiac output, which improves blood pressure, symptoms, quality of life, and patient compliance. All current registries consistently report that many patients with HFrEF are not receiving the target doses of b-blockers, even those without intolerance or contraindications. However, uptitration is often limited by undesired side effects, various clinical conditions, patients fears, and multiple comorbidities, which means that strict observance of current titration algorithms is a missed opportunity for optimal medical treatment. Research shows that an earlier administration of ivabradine improves b-blocker uptitration and helps reach therapeutic targets. In conclusion, the choice of drug association improves compliance, symptoms, and quality of life, which may reduce the hospitalization rate and mortality associated with heart failure. 1. Ponikowski P, Voors AA, Anker SD, et al ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2016;37(27): Böhm M, Swedberg K, Komajda M, et al; SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376(9744): Zugck C, Martinka P, Stoeckl G, et al. Heart rate control in chronic systolic heart failure patients in Germany: results of a nationwide survey. Eur Heart J. 2013;34 (suppl 1):P Bagriy AE, Schukina EV, Samoilova OV, et al. Addition of ivabradine to b-blocker improves exercise capacity in systolic heart failure patients in a prospective, openlabel study. Adv Ther. 2015;32(2): Strict observance of titration algorithms: a missed opportunity for optimal protection? MEDICOGRAPHIA, Vol 40, No. 1,

6 5. M. A. Saleh, Egypt Mohamed Ayman SALEH, MD, PhD Professor of Cardiology Ain Shams University Cardiology Department, Ain Shams University Abbaseya, Cairo, EGYPT ( Medications that improve prognosis for patients with heart failure are labeled as a class one indication in the European guidelines. Observations from daily clinical scenarios as well as small trials hint that there is room for changes that might affect patient outcomes. The guidelines specify target doses for b-blockers that should be reached gradually (if tolerated) over weeks to months, in 2-week increments. Around 8% of patients with heart failure do not receive b-blockers, which is usually due to the presence of contraindications, while 33% of the patients do not reach the target doses of b-blockers. 1 This is true for both hospitalized and ambulatory patients with heart failure. 1 A meta-analysis by McAlister et al provides evidence showing that the major benefit of b-blockers in patients with heart failure results from their effect on reducing heart rate. 2 Moreover, a higher heart rate is a mortality and morbidity risk factor that should be a target in itself. For every 5-bpm reduction in heart rate with a b-blocker, there is an 18% reduction in the risk of death. 2 Furthermore, there was no significant relationship between all-cause mortality and the dose of b-blockers achieved. 2 Ivabradine reduces heart rate and improves prognosis in heart failure patients without reducing blood pressure or cardiac output. In a subanalysis of the SHIFT study (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial), it was confirmed that the addition of ivabradine to b-blockers, rather than the dose of the b-blockers, was important in decreasing the rate of cardiovascular death and heart failure hospitalization. 3,4 In the current European Society of Cardiology heart failure management guidelines, ivabradine is indicated if heart failure symptoms persist and the heart rate is 70 bpm after reaching the maximally tolerated doses of b-blockers and angiotensin-converting enzyme inhibitors. Almost one-third of hospitalized and ambulatory patients with heart failure have a systolic blood pressure 110 mm Hg, which would further limit the uptitration of b-blockers. 1 The early use of ivabradine in the initial treatment of heart failure with b-blockers will increase the percentage of hospitalized and ambulatory patients with heart failure who achieve lower heart rates earlier in the heart failure journey. The weeks and months consumed trying to uptitrate b-blockers are precious, especially in hospitalized patients with heart failure because the first 30 days postdischarge carries the highest risk of mortality and readmission. 5 Adding ivabradine to the predischarge pharmacological cocktail would rapidly reduce heart rate hence breaking the high-risk loop. Of course there are gaps in knowledge due to the lack of large, randomized, head-to-head trials comparing b-blockers with ivabradine in hospitalized and ambulatory patients with heart failure. 1. Maggioni S, Anker S, Dahlström, et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with European Society of Cardiology guidelines? Evidence from 12,440 patients of the ESC Heart failure Long-Term Registry. Eur J Heart Fail. 2013;15(10): McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: b-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med. 2009;150(11): Böhm M, Swedberg K, Komajda M, et al; SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376(9744): Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Effects on outcomes of heart rate reduction by ivabradine in patients with congestive heart failure: is there an influence of beta-blocker dose?: findings from the SHIFT (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial) study. J Am Coll Cardiol ;59(22): Marti CN, Fonarow GC, Gheorghiade M, Butler J. Timing and duration of interventions in clinical trials for patients with hospitalized heart failure. Circ Heart Fail. 2013;6(5): MEDICOGRAPHIA, Vol 40, No. 1, 2018 Strict observance of titration algorithms: a missed opportunity for optimal protection?

7 6. P. V. Schwartzmann, Brazil Pedro V. SCHWARTZMANN, MD, PhD Coronary and Heart Failure Unit Clinical Hospital, Ribeirão Preto University of São Paulo BRAZIL ( Heart failure is a major public health problem that affects millions of people worldwide. Despite recent advances in the management of heart failure, this clinical condition is still associated with high morbidity and mortality and a high rate of rehospitalization. Evidence-based treatment is a life-saving strategy to reduce cardiovascular events. The guidelines for treating patients with heart failure with reduced ejection fraction (HFrEF) recommend starting with low does and uptitrating to maximal tolerated doses of neurohormonal antagonists, such as angiotensin-converting enzyme (ACE) inhibitors, b-blockers, and mineralocorticoid receptor antagonists (MRAs). However, in clinical practice, most patients with HFrEF do not attain guideline-recommended target doses. A previous prospective cohort study of patients with HFrEF in an outpatient setting found that only 27% of patients with heart failure received all heart failure therapies for which they were potentially eligible. 1 More recently, data from the BIOSTAT-CHF study (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) showed that patients who were treated with less than 50% of the recommended doses of ACE inhibitors and b-blockers have a greater risk of death and/or heart failure hospitalization. 2 Moreover, an international, prospective, longitudinal survey, QUALIFY (QUality of Adherence to guideline recommendations for LIFe-saving treatment in heart failure survey) recruited 6669 outpatients with HFrEF after a heart failure hospitalization to verify global adherence to guidelines for the prescription of ACE inhibitors, b-blockers, MRAs, and ivabradine. At the 6-month follow-up, poor adherence was associated with significantly higher overall mortality, heart failure mortality, and combined heart failure hospitalization or heart failure death 3 ; whereas, good adherence was associated with a better survival. Uptitration may be a lengthy process, involving numerous visits to the physician. Other factors may also contribute to the uptitration delay, such as low blood pressure, comorbidities, fatigue, and drug tolerability. Of note, a high percentage of patients with heart failure are unable to maintain the recommended b-blocker dose over time, even those followed in clinical trials. 5 A high resting heart rate is a strong predictor of worse morbidity and cardiovascular mortality in both general 6 and HFrEF populations. 7 Moreover, lowering the resting heart rate is a central target of heart failure treatment. Achieving a better control of the resting heart rate with b-blockers and ivabradine improves adverse outcomes in patients with HFrEF. 8 Data from the SHIFT trial (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial) showed that event rates of the primary composite end point (cardiovascular death or hospitalization) at the first 28 days of the study follow-up was significantly higher in patients with an elevated heart rate compared with those with a lower heart rate. 9 Thus, an absolute decrease in heart rate achieved with ivabradine reduces cardiovascular death and hospitalization rates early after the onset of the medication. 8,9 In conclusion, guideline-recommended therapy for HFrEF is frequently incompletely delivered to patients in real-world settings. Strict observance of the guidelines to achieve the maximal tolerated doses of neurohormonal blockade could take several months to reach target doses. During this period, patients are vulnerable to worse outcomes if their resting heart rate is elevated. Physicians should be aware of the very early clinical benefits of achieving a lower resting heart rate, and they should also realize that a lack of action in this scenario potentially results in an adverse prognosis. 1. Fonarow GC, Yancy CW, Albert NM, et al. Heart failure care in the outpatient cardiology practice setting: findings from IMPROVE HF. Circ Heart Fail. 2008;1(2): Ouwerkerk W, Voors AA, Anker SD, et al. Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study. Eur Heart J. 2017;38(24): Komajda M, Anker SD, Cowie MR, et al; QUALIFY Investigators. Physicians adherence to guideline-recommended medications in heart failure with reduced ejection fraction: data from the QUALIFY global survey. Eur J Heart Fail. 2016; 18(5): Verbrugge FH, Duchenne J, Bertrand PB, Dupont M, Tang WH, Mullens W. Uptitration of renin-angiotensin system blocker and beta-blocker therapy in patients hospitalized for heart failure with reduced versus preserved left ventricular ejection fractions. Am J Cardiol. 2013;112(12): Bagriy AE, Schukina EV, Samoilova OV, et al. Addition of ivabradine to b-blocker improves exercise capacity in systolic heart failure patients in a prospective, open-label study. Adv Ther. 2015;32(2): Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and cardiovascular mortality: the Framingham Study. Am Heart J. 1987;113(6): Pocock SJ, Wang D, Pfeffer MA, et al. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J. 2006;27(1): Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744): Böhm M, Swedberg K, Komajda M, et al; SHIFT Investigators. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376(9744): Strict observance of titration algorithms: a missed opportunity for optimal protection? MEDICOGRAPHIA, Vol 40, No. 1,

8 7. H. S. Sisakian, Armenia Hamayak S. SISAKIAN, MD, Professor, FAHA Head of Cardiology Department, University Hospital 1, Yerevan State Medical University Koryun street 2, Yerevan 0025 ARMENIA ( Heart failure (HF) decompensation represents a lifethreatening state, which requires careful clinical assessment and therapeutic intervention. Many such patients have a heterogeneous clinical pattern and treatment response that needs a personalized approach in addition to a guideline-based treatment. In patients with HF, a recent analysis showed that a heart rate >90 bpm at discharge was significantly associated with a greater risk of 30-day hospital readmission. 1 b-blockers remain the drugs of choice for lowering heart rate in patients with chronic HF with reduced ejection fraction (HFREF), but their use is suboptimal because many patients do not tolerate the guideline-recommended doses, which leads to inadequate heart rate control. The adverse effects of b-blockers are generally related to complications that arise from interfering with the adrenergic nervous system. Drugs that affect the renin-angiotensin-aldosterone system (RAAS) have unfavorable hemodynamic influences with decreases in blood pressure, worsening renal function, and hyperkalemia. Guideline-based treatment should be initiated at low doses followed by a gradual increase if well tolerated; however, unlike RAAS inhibitors, which may be uptitrated relatively rapidly, b-blockers should be uptitrated at 2-week intervals. Many patients are intolerant to b-blockers due to side effects, worsening fluid retention, symptomatic hypotension, and comorbidities, such as chronic obstructive pulmonary disease and periphery artery disease. Following discharge, undertreatment with b-blockers and RAAS inhibitors occurs frequently, ranging from 15% to 20% of discharged patients, particularly those with low blood pressure. 2 These patients have an increased risk of cardiovascular events and they need a heart rate lowering approach after hospital discharge. The SHIFT trial (Systolic Heart failure treatment with the I f inhibitor ivabradine Trial) showed that ivabradine substantially reduced the total number of HF hospitalizations by 25% and recurrent rehospitalizations by 34%. 3 Therefore, lowering heart rate in patients with HF without affecting blood pressure and contractility may reduce cardiovascular risk, particularly rehospitalizations. 4 Pathophysiological explanations of the effects of ivabradine may include improvements in intracardiac hemodynamics and diastolic function in patients with severely impaired systolic function by decreasing heart rate and prolonging the left ventricular filling period, leading to a subsequent decrease in the left atrial pressure and volume index. 5 The beneficial effect of ivabradine on diastolic filling parameters may potentially contribute to the better clinical outcome and prognosis in selected patients with a high heart rate and systolic HF. Several studies showed that, in patients with systolic HF, left atrial enlargement and left atrial pressure may serve as reliable markers and predictors of adverse cardiovascular events. 6,7 The influence of ivabradine and RAAS inhibitors on intracardiac hemodynamic parameters provides more clinical efficacy in patients with systolic HF. Optimization of pharmacotherapy in decompensated patients after hospital discharge should be carefully assessed, taking into consideration the possible intolerance to the components of neurohumoral inhibition of guideline-based therapy, hemodynamic state, comorbidities. To achieve a stable disease course in patients with systolic HF, it is recommended to provide pure heart rate lowering therapy in addition to b- blockers (at the highest tolerated dose) or alone (if contraindications to b-blockers are present) after hospital discharge. 1. Habal MV, Liu PP, Austin PC, et al. Association of heart rate at hospital discharge with mortality and hospitalizations in patients with heart failure. Circ Heart Fail. 2014;7(1): Gattis WA, O Connor CM, Gallup DC, et al; IMPACT-HF Investigators. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for assessment of Carvedilol Therapy in Heart Failure ( IMPACT-HF) trial. J Am Coll Cardiol. 2004; 43(9): Borer JS, Böhm M, Ford I, et al; SHIFT Investigators. Effect of ivabradine on recurrent hospitalization for worsening heart failure in patients with chronic systolic heart failure: the SHIFT study. Eur Heart J. 2012;33(22): Swelberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized placebo-controlled study. Lancet. 2010;376(9744): Sisakian HS, Sargsyan T, Khachatryan A. Effect of selective heart rate reduction through sinus node I f current inhibition on severely impaired left ventricular diastolic dysfunction in patients with chronic heart failure. Acta Cardiol. 2016;71(3): Abhayaratna WP, Seward JB, Appleton CP, et al. Left atrial size: physiologic determinants and clinical applications. J Am Coll Cardiol. 2006;20;47(12): Tsang TS, Abhayaratna WP, Barnes ME, et al. Prediction of cardiovascular outcomes with left atrial size: is volume superior to area or diameter? J Am Coll Cardiol. 2006;47(5): MEDICOGRAPHIA, Vol 40, No. 1, 2018 Strict observance of titration algorithms: a missed opportunity for optimal protection?

9 8. M. Zoghi, Turkey Mehdi ZOGHI, MD, FESC President of World Heart Failure Society Ege University, Department of Cardiology Izmir, TURKEY ( T he ESC guidelines recommend renin-angiotensin-aldosterone system (RAAS) blockers and b-blockers for the first-line chronic treatment of patients with heart failure, starting together and uptitrating to the maximum tolerated dose. 1 However, in real life, many patients are receiving doses that are lower than the recommended target doses. There are three main barriers to achieving the maximal target doses of neurohormonal and sympathetic antagonists: (i) physician-related (nonadherence to the guidelines, lack of patient follow-up); (ii) patient-related (age, blood pressure, renal function, poor adherence to medications); and (iii) drug-related (side) effects that are essential for the optimal management of patients with heart failure. Receiving suboptimal treatment is more common for b-blockers (14.8%) than for angiotensinconverting enzyme (ACE) inhibitors (27.9%), meaning that the debate concerning the importance of the target doses or achieved heart rate continues for b-blockers. 2,3 The SHIFT study showed that hypotension limits uptitration in 45% of cases and leads to intolerance in 20% of cases. 4 Side effects due to the negative inotropic effect of b-blockers limit their rapid uptitration; therefore, an agent that improves left ventricular function and increases stroke volume without negative inotropic effects would help achieve a higher b-blocker dose and provide optimal protection. Mulder et al 5 showed that ivabradine significantly reduced left ventricular endsystolic volume and increased stroke volume in vitro. Bagriy et al 6 showed that the early combination of ivabradine and carvedilol improved clinical outcomes (36%; P<0.05) within a shorter b-blocker uptitration period (1.9±0.4 vs 2.8±0.6 months; P<0.05) and higher dosages of carvedilol were achieved when combined with ivabradine vs carvedilol alone (37.8±13.9 mg/ day vs 30.9±15.3 mg/day; P=0.049). In the ETHIC-AHF study, despite the similar b-blocker doses at the end of the first year, cardiovascular death was 26% lower and the left ventricular ejection fraction was significantly higher (48.2±17% vs 41.8±10%; P=0.002) when ivabradine was administered early (24 to 48 hours after hospitalization) and combined with a b-blocker. 7 These reports may support the early combination of ivabradine and b-blockers. Adding a mineralocorticoid receptor antagonist (MRA) may be conceivable after the steps of obtaining maximum neurohormonal and sympathetic blockade (b-blocker + ivabradine) according to the following results: (i) in the SHIFT trial, the safety and effects of ivabradine on reducing the primary end point (cardiovascular death and hospitalizations for heart failure) were similar in patients with and without MRAs 4,8 ; (ii) in the PARADIGM-HF study, % of the enrolled patients had not received an MRA at baseline and hyperkalemia was significantly lower in the sacubitril/valsartan group than in the enalapril group (P=0.003) in patients who were newly started on an MRA during the study; (iii) the effects of b-blockers and/or MRAs were recently reported to be different in patients with concomitant atrial fibrillation and heart failure with reduced ejection fraction (HFrEF); and (iv) b-blockers had no effect on mortality 3 and total mortality increased 1.4-fold with MRAs. 10 In conclusion, adding ivabradine to low doses of b-blockers may be an acceptable strategy vs slowly uptitrating b- blockers to the maximum dose, and as the effects of neurohormonal and sympathetic inhibitors are not the same in all patients with heart failure, the priority of targets for optimal protection should be individualized. 1. Ponikowski P, Voors AA, Anker SD, et al ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 2016; 18(8): Ouwerkerk W, Voors AA, Anker SD, et al. Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study. Eur Heart J. 2017;38(24): Kotecha D, Flather MD, Altman DG, et al; Beta-Blockers in Heart Failure Collaborative Group. Heart rate and rhythm and the benefit of beta-blockers in patients with heart failure. J Am Coll Cardiol. 2017;69(24): Swedberg K, Komajda M, Böhm M, et al; SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744): Mulder P, Barbier S, Chagraoui A, et al. Long-term heart rate reduction induced by the selective If current inhibitor ivabradine improves left ventricular function and intrinsic myocardial structure in congestive heart failure. Circulation. 2004;109(13): Bagriy AE, Schukina EV, Samoilova OV, et al. Addition of ivabradine to b-blocker improves exercise capacity in systolic heart failure patients in a prospective, open-label study. Adv Ther. 2015;32(2): Hidalgo FJ, Anguita M, Castillo JC, et al. Effect of early treatment with ivabradine combined with beta-blockers versus beta-blockers alone in patients hospitalised with heart failure and reduced left ventricular ejection fraction (ETHIC- AHF): A randomised study. Int J Cardiol. 2016;217: Komajda M, Böhm M, Borer J, et al. Influence of background treatment with mineralocorticoid receptor antagonists on ivabradine s effects in patients with chronic heart failure. Eur J Heart Fail. 2013;15(1): Desai AS, Vardeny O, Claggett B, et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: a secondary analysis of the PARA- DIGM-HF Trial. JAMA Cardiol. 2017;2(1): O Meara E, Khairy P, Blanchet MC, et al; AF-CHF Investigators. Mineralocorticoid receptor antagonists and cardiovascular mortality in patients with atrial fibrillation and left ventricular dysfunction: insights from the Atrial Fibrillation and Congestive Heart Failure Trial. Circ Heart Fail. 2012;5(5): Strict observance of titration algorithms: a missed opportunity for optimal protection? MEDICOGRAPHIA, Vol 40, No. 1,